Post COVID-19 condition among adults in Malaysia following the Omicron wave: A prospective cohort study

Post COVID-19 condition is an important public health problem as we emerge from the COVID-19 pandemic. In this prospective cohort study, we aimed to determine the prevalence of this condition and assess its associated factors and impact on health-related quality of life in a population setting in Malaysia. Study was conducted from April to June 2022 when the Omicron variant predominated. All individuals testing positive for SARS-CoV-2 infection (RT-PCR, RTK-Ag) were invited for participation. Study questionnaires were delivered via the MySejahtera platform (mobile application). From the total of 44,386 participants who provided responses up to 3-months interval, 1,510 participants (3.4%) fulfilled the post COVID-19 condition criteria. Majority of the affected participants (83.8%, n = 1,265) experienced either cough, fatigue or forgetfulness–the three most common symptoms. Being females, having existing comorbidities, presence of symptoms and requiring hospital admission during the acute illness were associated with higher likelihoods of developing the post COVID-19 condition at 3-months interval. Amongst the 1,510 individuals, one in five had limitations in performing their usual daily activities while at least one in three expressed that their work was affected. Understanding this condition better is essential to guide strategic and responsive plans of action, which may require coordinated multidisciplinary interventions.

This persistence of symptoms in some individuals following coronavirus disease 2019 (COVID-19) was referred to by several common terms including long COVID, long haulers, post-acute COVID-19 syndrome, post-acute sequelae of COVID-19 (PASC), and post COVID-19 condition [15][16][17][18][19].The World Health Organization (WHO) using the Delphi consensus methodology recently developed a clinical case condition for this "post COVID-19 condition", defined as the continuation or development of new symptoms three months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least two months with no other explanation [3,19].
Existing studies on this condition mostly involved hospitalised individuals (more severe forms of acute  and earlier variants of SARS-CoV-2, particularly the Delta variant [9,20].A meta-analysis of 41 studies has estimated the pooled prevalence of this condition at 43% (95% CI 39%, 46%) [21], but most of the studies included preceded the Omicron variant surge.This gap, together with studies demonstrating the impact of COVID-19 vaccination on post COVID-19 condition [2,22,23], necessitates further assessment of this condition given the overwhelming proportion of recent SARS-CoV-2 infections contributed by the Omicron variant and the increasingly vaccinated populations against COVID-19 globally.This is also especially important for low-and middle-income countries (LMICs), where reported studies are notably scarce [9].
Malaysia is an upper-middle-income country with an estimated 32.9 million population in 2022 [24].More than 95% of the adult population in Malaysia were fully vaccinated against COVID-19 by the end of 2021 [25] but like many other countries globally, Malaysia was not spared by the Omicron variant onslaught.In January 2022, the Omicron variant had contributed to 80% of the samples sequenced under the genomic surveillance in Malaysia [26].A surge of confirmed COVID-19 cases then ensued from February to March 2022, where over 20,000 cases/day were recorded on average [27].Cumulatively, as of December 2022, over five million confirmed cases of SARS-CoV-2 infections have been documented in Malaysia [28].
Although the majority of the COVID-19 cases reported full clinical recovery, given the backdrop of an ageing society [24] and the significant burden of non-communicable diseases (NCDs) among the population in Malaysia, particularly for cardiovascular diseases, diabetes and cancer [29,30], an assessment of the burden and impact of this post COVID-19 condition is warranted.The present study, therefore, aims to determine the prevalence of post COVID-19 condition in a population setting in Malaysia following the Omicron wave of SARS-CoV-2 infections, by using the recent WHO definition for this condition.We also aimed to assess the factors associated with the development of this condition and its impact on health-related quality of life amongst those affected.

Study design and data collection
This was a prospective, observational cohort study conducted nationwide in Malaysia.All individuals aged 18 years and above who tested positive for SARS-CoV-2 infection between 23 rd April 2022 and 24 th June 2022, either via reverse-transcriptase polymerase chain reaction assay (RT-PCR) or rapid test kit for antigen testing (RTK-Ag), were invited for participation in the study.The diagnosis and testing did not include the type of variant, as routine genomic surveillance is not performed in Malaysia.In a previous study, 5 th February 2022 was estimated as the start of the pre-dominant Omicron period in Malaysia by using the Bai-Perron sequential breakpoint test [25] and therefore, the Omicron variant is presumed to be the predominant variant in circulation during this study.
All study participants provided voluntary informed consent before a self-reported online study questionnaire was administered seven days after the date of the positive test.This assessment at baseline constituted the acute phase of illness following the SARS-CoV-2 infection.Participants were then followed up at 1-month, 3-months and 6-months intervals, similarly via self-reported questionnaires, to assess for the continued presence of symptoms (if any) and its impact on health-related quality of life.The informed consent procedure, as well as all data collection in this study, were done electronically and utilised the MySejahtera platform (mobile application).Mysejahtera platform was developed to assist the management of the COVID-19 pandemic in Malaysia with functions including uploading and tracking of risk status, testing and results for SARS-CoV-2 infection, self-health assessment and status monitoring, as well as COVID-19 vaccination appointment and certificate [31].The platform was available for free and was widely used by the Malaysian public.

Study measures and operational definition
Study questionnaire was developed by adapting findings from a literature review on the frequent symptoms of COVID-19 and gathering consensus from local experts in infectious diseases, epidemiology, public health and clinical research.There were three main sections of the questionnaire: the first section collected demographic characteristics and underlying medical co-morbidities; the second section captured the presence of COVID-19 related symptoms, while the third section contained questions on the impact of COVID-19 on the health-related quality of life of the individuals-including on their mobility, self-care, activities of daily living, emotions and ability to (return to) work.Study questionnaire at baseline is provided in the S1 File.
In Malaysia, the clinical management of confirmed COVID-19 cases in adults follows the guidelines by the Ministry of Health Malaysia [32].This included the consideration and criteria for hospital admission.Further details on the hospital admission, including the clinical staging of cases, are provided in the S2 File.
The definition of study outcome of interest, or "post COVID-19 condition", adapts the clinical case definition developed by the WHO [19].In this study, to fulfil the criteria of "post COVID-19 condition", an individual must have had continuing symptoms or developed new symptoms three months after being diagnosed positive (RT-PCR or RTK-Ag) for SARS-CoV-2 infection, and the symptoms needed to last for at least two months duration.

Statistical analysis
Demographic and clinical characteristics of participants were described as counts with percentages for categorical variables and means with standard deviations for continuous variables.Prevalence of post COVID-19 condition and prevalence of specific COVID-19 related symptoms were reported based on the number of participants with the condition during the followup period.McNemar's test was used to compare health-related quality of life measures among individuals with post COVID-19 condition at baseline and after 3-months.Logistic regression was performed to identify factors potentially associated with post COVID-19 condition.The dependent variable was the presence of post COVID-19 condition.Independent variables were identified based on prior knowledge and clinical relevance.Univariate logistic regression analysis was conducted by including each variable separately in the models and variables with p-value less than 0.25 were entered into the multivariable model.Adjusted odds ratio and the corresponding 95% confidence intervals were estimated based on multivariable logistic regression model and correction for multiple testing by the Holm method.Variables were checked for multicollinearity and assumptions for the regression model.Statistical significance was set at p-value less than 0.05.All analyses were conducted using R version 4.1.2in R Studio.

Ethical consideration
Participants' informed consent were obtained electronically via the Mysejahtera platform (mobile application).All data collected for the purpose of the study was deidentified.Study was registered in the National Medical Research Register (NMRR-21-880-59662) and ethical approval for study conduct was granted by the Medical Research and Ethics Committee (MREC), Ministry of Health, Malaysia.

Results
A total of 124,937 participants completed the study questionnaire during baseline (seven days after being diagnosed positive for SARS-CoV-2 infection).Subsequently, 79,474 participants (63.6%) responded during the 1-month interval and 44,386 participants (35.5%) responded during the 3-months interval, which were included in the final analysis (Fig 1).Table 1 describes the socio-demographic and COVID-19 characteristics of all the participants.Amongst the 44,386 participants at 3-months follow-up included in the final analysis, the majority of them were females, aged between 30 and 59 years old, received at least secondary education and had been fully vaccinated against COVID-19.Medical comorbidities were present in around a quarter of the participants (25.7%, n = 11,422), with obesity, hypertension and diabetes mellitus being the most common.Within this cohort of 44,386 participants, 10,194 (24.6%) of them were symptomatic during the acute phase following SARS-CoV-2 infection while 1,088 (2.5%) of them were admitted to hospital, 268 (0.6%) needed supplemental oxygen and 122 (0.3%) required intensive care unit (ICU) admission.
In the multivariable logistic regression (Table 2), age group 30-59 years old (compared to 18-29 years old), females (compared to males), presence of comorbidities, presence of symptoms and requiring hospital admission during the acute infection were found to have higher odds for the development of post COVID-19 condition.Being symptomatic during the acute infection was associated with an estimated 13 times higher odds (adjusted odds ratio 13.3, 95% CI 11.7, 15.2) higher odds for post COVID-19 condition.In contrast, the elderly age group (60 years and above) and being of other ethnicities had lower odds of developing the post COVID-19 condition.These factors remained significant after correction for multiple testing by the Holm method.
The final section of the study questionnaire captured the impact of post COVID-19 condition on the participants' health-related quality of life (Table 3).At 3-months interval following SARS-CoV-2 infection, amongst the 1,510 participants who had post COVID-19 condition, 10.3% (n = 155) had symptoms limiting their mobility (walking), 1.5% (n = 33) had symptoms limiting their ability for self-care and hygiene, 22.1% (n = 333) had limitations in performing usual activities (housework, participation in family or leisure activities), 7.6% (n = 115) cannot live alone without any assistance from another person and 33.8% (n = 511) experienced symptoms that led to negative emotions such as sadness, anxiety and depression.Further, 54.0% (n = 816) of participants who had the condition reported that their work was unaffected at 3-months interval, 38.7% (n = 584) expressed that their work was affected but still able to continue working while 1.3% (n = 19) either lost their job or had to change job(s).Findings were largely similar to those reported at baseline during the acute phase following the SARS-CoV-2 infection, indicating that the impact lasted through for at least three months.

Discussion
In this study, we found that 3.4% of study participants fulfilled the criteria for post COVID-19 condition during a period where SARS-CoV-2 infections in Malaysia and globally were of Omicron variant predominance.Our final analysis, however, utilised data up to 3 months only following SARS-CoV-2 infection as by this duration, the attrition rate of participants' responses had reached 64.5% from baseline.This was partly attributed to the declining usage of the MySejahtera app by the public from May 2022 onwards, as registering check-ins to physical premises (one of the app's core functions) was no longer mandatory nationally [27,33].Nevertheless, in our final cohort of 44,386 participants, there was a fair distribution across all groups in the socio-demographic and COVID-19 characteristics, and the characteristics were largely similar to the overall patients recruited at baseline (Table 1).Similar studies elsewhere have reported varying findings on the prevalence of this condition.Compared to earlier studies, recent studies that included cases from Omicron predominant periods have reported lower estimated rates of post COVID-19 condition [20,34,35].A previous study conducted in Malaysia involving 732 COVID-19 survivors in the community before the emergence of Omicron reported a higher prevalence rate of 21.1% [10].The  observed lower rate of 3.4% in our study can be explained in part by the decreased likelihood of post COVID-19 condition during periods when the Omicron variant predominated [20,34,36], as well as amongst those who are vaccinated [2,22,23].Our study also followed the recent WHO definition for post COVID-19 condition [19], which may predate some of the earlier studies.It is prudent to consider factors such as the varying definitions and methods used to estimate the prevalence, varying length of follow-up periods involved, the predominant variant in circulation, as well as the different healthcare settings or populations included in the studies [7,21,37,38] when comparing rates and findings across studies.Although the estimated rates in studies following the Omicron wave appear to be lower, it is crucial to note the number of confirmed COVID-19 cases following the Omicron wave has exceeded that of all previous variants [36].Therefore, an overall high burden in the number of people to be affected by the post COVID-19 condition is possible.To illustrate an example, as of November 2022, the UK COVID-19 Infection Survey Data estimated that 2.1 million people living in private households in the UK (3.3% of the population) to be experiencing selfreported long COVID symptoms for more than four weeks following infection [39].In Malaysia, although over five million confirmed COVID-19 cases have been documented by 2022 [28], the total number of actual infections may likely be higher [40].
Next, our study embarked on describing the persistent symptoms experienced and identifying groups at higher risk for the post COVID-19 condition.The persistent symptoms involving multiple organ systems that are self-reported by the participants in this study are consistent with findings by numerous studies and reviews elsewhere [1,2,[4][5][6][7][8][9][10][11].A salient observation in our study was that an overwhelming proportion of the participants (83.8%, or more than four in five participants) reported at least one of the three most common symptoms-cough, fatigue and forgetfulness.Given the long list of related symptoms and the absence of a gold standard for evaluation and diagnosis of post COVID-19 condition, the assessment of these three symptoms may be useful to be incorporated in early screening initiatives in the future, as well as aiding efforts in risk communication and health education for the public.Further research in this aspect should be encouraged.
Our study also looked into identifying groups at higher risk of developing post COVID-19 condition and found several significant factors.Both the presence of symptoms and requiring hospital admission during the acute phase of illness (when participants were first diagnosed positive for COVID-19) had been observed to be associated with higher likelihoods of developing the post COVID-19 condition.This is consistent with findings from existing studies, where the presence (and number) of symptoms and severity of COVID-19 have been implicated [10,15,20,[41][42][43][44].The higher odds observed in this study for being symptomatic, as compared to hospital admission, suggests that many who experienced mild COVID-19 may still experience persistent symptoms for up to three months duration.
We found that female participants had higher odds for post COVID-19 condition, which is consistent with findings elsewhere [10,15,34,35,44].Differences in immune system function and sex hormones contributing to asymmetry in risk outcomes between sexes may be important drivers underlying the sex differences in post COVID-19 condition [45][46][47].Although previous studies have observed that the condition increased with age [34,41,44], our observation for age in this study was not consistent.Although those who were aged 30-59 years old had higher odds compared to 18-29 years old, the elderly group aged 60 years and above were observed to have lower odds.This could have been due to the lower participation of the elderly group of participants, as most of the participants in this study were in the younger age groups.Malaysia has a high NCD burden, with an estimated 1 in 3 adults living with hypertension, 1 in 5 adults living with diabetes and nearly half of the adults are overweight and obese [29,30].Our study cohort may be mostly in younger age groups with fewer comorbidities, but the finding that the presence of comorbidities increases the chance for post COVID-19 condition calls for concern given the high NCD burden amongst the general population in Malaysia.Similarly, other countries with significant NCD burdens should also be forewarned.This association between comorbidities and the post COVID-19 condition has also been reported in other studies [18,35].
Identifying groups, or risk factors that increase the likelihoods of developing post COVID-19 condition is crucial to guide efforts in managing the condition, particularly in risk stratification as well as resources planning and allocation.In particular, findings from this study which was conducted in a population setting will be useful to provide a better overall picture of risk factors in the general public, compared to studies which are conducted among hospitalized or care-seeking populations as they may overrepresent those with comorbidities or at more severe spectrum of COVID-19.
In the final section of our study questionnaire, we evaluated the impact of this condition on the health-related quality of life.Notably, we found that at least one in five participants who were affected by post COVID-19 condition had limitations in performing usual daily activities, one in three had negative emotions such as sadness, anxiety and depression and around 40% of the participants reported that their work was affected.In another local study, a third of the participants who were COVID-19 survivors reported that their work performance was affected [10].The impact on work and productivity may eventually lead to economic implications, especially since studies have reported that symptoms may continue to be present one to two years after COVID-19 diagnosis [12,[48][49][50].
Our study has several limitations.First, data collection was performed via a self-reported online questionnaire administered via a mobile application and therefore an objective assessment of the participants' condition was not carried out.We were unable to conclusively rule out any alternative diagnosis which may otherwise explain the symptoms that were present.Second, as the majority of the participants in this study were at least fully vaccinated against COVID-19, we could not investigate the effect of vaccination on the post COVID-19 condition.Earlier studies have demonstrated that receipt of vaccines was associated with reduced risk of this condition [22,23].
Overall, findings from this study underscore the gravity and impact of post COVID-19 condition as an important public health problem as we emerge from the COVID-19 pandemic; requiring strategic and responsive actions.As the symptoms cut across multiple organ systems, management of individuals affected by this condition will likely require, or benefit from, dynamic and coordinated cross-sectoral interventions involving multiple specialties.Additionally, previous studies have also highlighted that efforts and services should be all-encompassing, catering for physical or biological, psychological or experiential, social or environmental, informational as well as spiritual needs of the patients [13,51].In this regard, the living guidance for clinical management of COVID-19 by the WHO [52] provides recommendations and guidance for a comprehensive and holistic management plan to safeguard optimal and continuing care for COVID-19 patients.In Malaysia, efforts are ongoing-this includes putting in place a multidisciplinary management protocol for post COVID-19 patients [53] as well as rehabilitation framework models for both inpatient and outpatient services [54].